Receptor tyrosine kinases are transmembrane proteins that participate in cell signal transduction. Specifically, they transmit growth factor signals from the cell surface to certain intracellular processes that control critical function such as growth, differentiation and angiogenesis. A. A. Adjei, Drugs of the Future 2001, 26(11):1087–1092.
Many cancers are associated with aberrant signaling. In particular, deregulated signaling via tyrosine kinases plays a key role in the growth and spread of cancers. A. D. Laird and J. M. Cherrington, Expert Opin. Invetig. Drugs, 2003, 12(1):51–64. One family of receptor tyrosine kinases is the epidermal growth factor receptor (EGFR) tyrosine kinase. These receptors have been found to be over expressed in a number of epithelial cancers and have been implicated in tumor aggressiveness.
The role of receptor tyrosine kinases (RTKs), and in particular of EGFR, in the growth and spread of cancers is well established. See, Laird and Cherrington, supra; and Adjey, supra. There is thus extensive research to develop small molecule inhibitors of RTKs, and in particular of EGFR. For reviews of compounds inhibiting EGFR and their therapeutic use see Laird and Cherrington, supra; Adjey, supra; Drugs of the Future 2002, 27(4):339–345; M. R. Myers et al., Bioorganic & Medicinal Chemistry Letters, 1997, 7(4): 421–424; A. J. Bridges et al., J. Med. Chem., 1996, 39:267–276; G. W. Rewcastle et al., J. Med. Chem. 1995, 38:3482–3487